Cells arrested in the plateau phase in vitro resemble the nondividing G(0) compartments described in vivo for stem cells and for cells in the viable, but nondividing fractions of some solid tumors. The reentry kinetics of plateau cells in vitro into the cell cycle mimics the recruitment of in vivo G(0) cells back into the dividing compartment. In addition the in vitro plateau phase survival responses to several cancer chemotherapy drugs have been confirmed with G(0) cells in vivo, as has the recovery from drug induced damage. Success or failure of cancer chemotherapy depends in part on the interactions of drugs with specific targets within the tumor cells. The effectiveness of therapy also depends upon the choice of drug, sequence of administration with other drugs, time between drug exposures, and the cell kinetics properties of the tumor (or test cells) being treated. This suggests that through a better understanding of these parameters, one might design and test more effective drug treatment combinaitions. It will be the purpose of ths proposal to investigate the specific effects of drugs on survival and cell kinetics of dividing and nondividing cells; and to determine whether cells can recover from drug-induced damage. Utilizing data from such experiments we will design and test drug combination treatments in CHO and human tumor cultures. The scheduling and choice of the second drug treatment will depend upon the response exhibited by cells after exposure to the first drug. This objective will be focused primarily on two areas-- drug combinations to inhibit repair or recovery, and drug combinations administered by kinetics-directed treatment schedules. The long term goals are that the results obtained in this proposal might suggest the design of more relevant and effectrive cancer chemotherapy protocols in man, in which the choice of drug, schedule and sequence of administration are based on specific experimental evidence.